DE2702509A1 - 17ALPHA-ESTERS OF GESTAGENS WITH ANTITUMOR EFFECTIVENESS, THEIR PRODUCTION AND AGENTS CONTAINING THESE ESTERS - Google Patents

Description

Aktlebolaget Leo, HeIsingborg, Sweden

170C esters of gestagens with anti-tumor activity, their preparation and compositions containing these esters

The present invention relates to novel 17 <X esters of Progestogens, which have an anti-tumor effect, and Method of making the same. The invention also includes pharmaceutical compositions comprising the aforesaid Contain compounds, and methods of treatment performed with them.

It is known that esters of certain steroids with alkanoarboxylic acids containing a phenyl group, which is substituted by a bis (2-chloroethyl) amino group, an antitumor effect on animal and racial Exercise living beings. The acidic part of these known esters consists mainly of 4- / fN, N-bis- (2-chloroethyl) -amino_7-phenylacetic acid and 4- ^ f "4- (N, N-bis- (2-chloroethyl) · amino) -phenyl_7-butyric acid passed.

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The types of steroids that have been studied include estrogens, androgens, corticoids, and one sterol, cholesterol. The hydroxy group or groups in these steroids that have been esterified were in one or both of them Positions 3- (estrogen), 3ß- (androgens, pregnenolone and cholesterol), 17β- (estrogens and androgens) and 21- (corticosteroids).

Such esters are described, for example, in J. Med. Chem. 11 _- (1968) II06, ibid. 12, (1969) 810, ibid. 1 £ (1972) II58 and in US Pat. No. 3,732,260.

There are no known esters of gestagens which have an alkylating group in their acid part, such as the bis (2-chloroethyl) amino group, Although numerous gestagens are known to contain the esterifiable hydroxy groups in various Have positions of the steroid molecules, e.g. in the 3, 11, 16 and 17 positions, and are even less any flestagenester are known in which the esterification has occurred in the position required for the present invention is of particular importance, namely in the 170C position.

It has now surprisingly been found that the the present invention underlying esters, which are 17 <* esters of gestagens, against tumors of Animals are effective and that they have a very low toxicity at the same time, resulting in extremely beneficial therapeutic Indioes leads.

The esters according to the invention are of importance in the treatment of tumors, e.g. those of the urogenital organs, like the ovaries, the endometrium, the prostate, the urinary

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bladder and kidneys. The compounds are particularly useful for the treatment of tumors which are located in organs which are receptors for progestins, like the endometrium and mammary glands. The compounds of the invention are also of great value for the treatment of haematological disorders.

The new YJOC esters of the gestagens according to the invention correspond to the general formula given below

The compounds of the invention have been found to be effective in inhibiting the growth of Tumors such as Ehrlioh ascites tumor, Harding-Passey melanoma, hepatoma AH 130, lymphocyte leukemia (L 1210) and the Walker-Caroinoms 256, with help the procedures as defined by the Cancer Chemotherapy National Service Center (see Cancer Chemotherapy Reports, January 1959 and December 1962).

As has also been found, the compounds according to the invention also have a high affinity for specific substances Progestin binders, i.e. receptors, in the cell cytoplasm.

The compounds according to the invention can be used in diseases which respond to treatment with anti-tumor agents and with immunosuppressive agents, either alone or combined with solid or liquid carriers or diluents, and they can be made available in varying amounts in pharmaceutical application forms, such as tablets, pills, Capsules, pellets, 'powders, ointments, suppositories, aqueous

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or non-aqueous suspensions and non-aqueous solutions.

Accordingly, it is an object of the present invention to provide new compounds which the Formula I below correspond and lower the aforementioned effectiveness and at the same time preferably one Show toxicity level.

Another object of the invention is to provide new compounds corresponding to the general formula XV below correspond, and also to make methods for their production available. These new connections are technical useful as intermediates for the preparation of the new compounds of general formula I in which the symbol m equals 1.

The present invention accordingly relates to new compounds corresponding to the general formula

St-R I

correspond, in which R is a group of the formula

-O- (LY) _m -C- (A) _k - (X) _n .

denotes in which R is a β- or γ- halogen-substituted alkyl group having 2 to 4 carbon atoms in which the halogen consists of chlorine or bromine; R represents a hydrogen atom, a low molecular weight alkyl group, a low molecular weight alkoxy group or a halogen atom; A denotes a straight-chain hydrocarbon chain with a maximum of 4 carbon atoms which is either saturated

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or has a double bond, with at most two hydrogen atoms from A through low molecular weight alkyl groups can be substituted and at most one of the hydrogen atoms that are adjacent to the carbon atom a -CO group can be replaced by an amino group or a low molecular weight alkanolamino group; furthermore, B stands for a straight-chain, saturated hydrocarbon chain with a maximum of 4 carbon atoms and at most 2 hydrogen atoms of B can be substituted by a low molecular weight alkyl group; X and Y independently of one another are -0-, -NH- and -S radicals; k, m and η independently represent the number zero or 1 represent with the proviso that η is always zero when k and m are zero; and finally St for that Remainder of a steroid that has a cyolopentanophenanthrene carbon-carbon skeleton has, which - including the substituents - a maximum of 40 carbon atoms contains, said carbon-carbon skeleton of a steroid nucleus from either pregnan or 19-norpregnan nuclei exists, which have zero to a maximum of 4 double bonds, said steroid residue at its 17-position is bound to R, said position being defined in terms of the usual steroid nomenclature.

The present invention also relates to new compounds which can be used as intermediates in the preparation of anti-tumor compounds of the formula I are technically useful and those themselves of the general formula

St-OCBR ¹⁰ XV

correspond, in which St and B have the meanings given above and the remainder St in its 17-position to the

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group

-O-ö-BR ¹⁰

is bonded, where R is a hydroxy or mercapto group or a hydroxyl or esterified by a carboxylic acid or a sulfonic acid having a maximum of 15 carbon atoms Means mercapto group or an amino or acylamino group having at most 15 carbon atoms or an azido group. If R stands for an amino group, this also includes those heterocyclic compounds which have a cyclization reaction of said group and the keto group in the 20-position of the steroid molecule is formed will.

In this description of the invention, the term "low molecular weight" means that the group hereby designated Has 1 to 4 carbon atoms inclusive. Therefore belong to the low molecular weight alkyl, alkoxy and alkanoyl groups the residues: methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, Isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, Acetyl, propionyl, butyryl and isobutyryl.

The nomenclature used in this description of the invention follows the "IUPAC 1957 Rules, for Nomenclature of Steroids". Wherever the general formulas I and XV and the symbols A, B, X, Y, R ¹ , R ² , R ¹⁰ , St, k, m and η are used in this description of the invention, they have the meanings given above.

Among the compounds which are encompassed by the above general formula I, those are preferred

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Question «in which the halogen atom of R is in the ß-position and the alkyl group of R selected from ethyl, n-propyl or n-butyl consists.

Compounds in which R stands for a -CHg-CHg-Cl- group, are particularly beneficial.

The group -NR ₂ is preferably in the m- or p-position, especially when k and η are equal to zero, and in ρε division when at least one of the symbols k and η is equal to 1.

ρ
It is advantageous if R stands for a hydrogen atom or a low molecular weight alkyl group.

If the -NR _o -group is in the m-position, then it is recommended-

2
It is advisable if R is in the p-position and is different from hydrogen, in particular if k and η are equal to zero.

Extremely highly effective compounds are obtained when m is equal to 1, and the configurations based thereon of the invention preferably come into embossing.

Is A through an amino group or a low molecular weight alkanoyl group substituted, then it is advantageous «if η is zero and A is from a saturated hydrocarbon chain, which contains 2 carbon atoms.

It is advantageous if η is zero.

The symbol X stands in the case in which it is present, preferably for -O- or -NH-, and in particular for -O- when k is equal to 1.

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If m and η are 1 and k are zero, then there will be connections obtained with extremely potent metabolites.

Only in the event that the in vivo stability of the If connections are desired, it is recommended that m be zero, and such connections have a exceptionally low toxicity.

It is advantageous if Y is -0- or -NH-.

If k is equal to 1, then it is particularly advisable if Y equals -0-.

Among the compounds encompassed by the above general formula XV, those are preferred as intermediates in question, in which R is a hydroxyl group or a carboxylic acid with at most 10 carbon atoms denotes an esterified hydroxyl group or an amino or acid group.

The steroid residue St, as defined above, has a carbon-carbon skeleton, which is preferably from the carbon-carbon skeleton of the Pregn-4-ene, Pregna-4,6-diens or 19-norpregn-4-ens.

The preferred nuclei of the said steroid residue which has one of the above-mentioned skeletons include 17o < -Pregn-4-en-3,20-dior>, 17 <X -Pregna-4,6-diene-3,20 -dione and 17oC - (19-norpregn-4-en-3,20-dione) nuclei in which the radical R is bonded to said 17-position.

Any further substitution that occurs in the carbon-carbon skeletons of the aforementioned steroid

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nuclei is present, at most a tetrasubstitution, with those positions in the steroid-carbon-carbon skeleton which are substituted, the 1-, 2-, 6-, 7-, 16- and 21-positions, and at least one substituent preferably consists of a methyl, ethyl or methylene group or a fluorine or chlorine atom. It is particularly recommended that said substitution be at most a disubstitution and include one or two substituents consisting of a 6-methyl, 6-chloro, 6-fluoro, 1,2-methylene or 16-methylene group.

The steroid residue (St) is preferably derived from the following steroids:

UCK -hydroxypregn-4-en-3 »20-dione (17 <X -hydroxyprogesterone), 17 <X -hydroxy-lOf-norpregn-Jl-en -;} * 20-dione, 6 (X -fluor- ^ ÖC -hydroxypregn ^ -en-}, 20-dione, 6 oi. -Chlor-ITOC-hydroxypregn- ^ en-}, 20-dione, 17oC -hydroxy-6o <-methylpregn- ^ en-}, 20-dione (medroxyprogesterone ),

17OC-Hydroxy-6o < _r 160 <-dimethylpregn-4-en-3,20-dione, YJoC -Hydroxypregna -4,6-diene-3,20-dione, 6-fluoro-17 <X -hydroxypregna-4, 6-dlen-3 »20-dione, 6-chloro-17iX -hydroxypregna-4,6-dlen, 5 * 20-dione (chlormadinone), YJCi -hydroxy-o-methylpregna ^, 6-diene-j5> 20- dione (Megestrol), 6-chloro-170 <'-hydroxy-10 ^, 2 0 (-me thylenpregna-4,6-diene-J, 20-dione (cyproterone),

6-chloro-17of -hydroxy-16oC-methylpregna-4,6-diene-3,20-dione, 6-chloro-17 (X-hydroxy-16-methylenpregna-4,6-diene-3,20-dione, IJ (X. -Hydroxy-6,16o (-dimethylpregna-4,6-diene-5,20-dione, 6-fluoro-17oC-hydroxy-16-methylene-9β, 10OC-pregna-4,6-diene- 3,20-dione,

6-fluoro-17o <-hydroxy-1ß, 2ß-methylene-9ß, 10 <X -pregna-4,6-diene-3 » 20-dione.

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Among the steroids listed above are preferred the 170 ^ -hydroxyprogesterone, medroxyprogesterone, chlormadinone, Cyproterone and megestrol in question.

In the following, references are given in the form of superscript, underlined numbers, e.g. in the form "these

■ ι Q

Method - is ... ". These numbers refer to literature sources that follow the examples in the form of a List are compiled.

As far as the procedures for the preparation are concerned, the compounds of structural formulas I and XV can under Application of conventional working methods can be obtained.

A general procedure (Working Method 1 below) for making the compounds represented by Formula I. is the following:

Working method 1

A compound of Formula I is prepared by reacting a 17-hydroxysteroid of Structural Formula III or of a reactive derivative thereof with an acid of the formula IV or a reactive derivative such (see e.g. references 1 and 2 on the esterification of 17-hydroxysteroids).

St - OH III

HO- (CBY) -O- (A) ₁ - (XL / (-5- \ R * IV

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Of the other working methods for making connections, corresponding to Formula I, the following can be given.

Working method 2

By reacting a 17-hydroxy ester of a steroid, wel cher of structural formula II, with an acid of formula V or a reactive derivative thereof

St-OCBR ⁵ II

the compound of the formula I is obtained in which m is equal to 1 is. R ^ herein means a group which, together with a -COOH group is able to form the group -Y-CO- in one stage or in several stages *

Working method 3

By reacting a halide of the formula VI with a compound of the formula VII or a reactive derivative the same

St-0- (C _r BY) _m -C- (A) _k -halogen Vl

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VII

a compound of the formula I is obtained in which η is the same is.

The word "halogen" used in this description of the invention means chlorine or bromine.

Working method k

It becomes a 17-hydroxysteroid that has structural formula III corresponds and in which a hydrogen atom in the 21-position is replaced by a hydroxyl group, reacted with a suitable derivative of acid IV to form a 17 »21-orthoester (for the preparation of orthoesters, reference is made to reference literature 3).

The 17.21 orthoester is then made according to procedures known per se converted into a compound of the formula I (see. Regarding the conversion of 17,21-orthoesters in 17 monoesters the reference literature 4).

A general method for preparing compounds of Formula XV is as follows.

Working method 5

By reacting a compound of the formula III or a reactive derivative thereof with an acid XVI or a reactive derivative thereof

HOOC-BR ¹¹ XVI

to obtain a compound of the formula XV or a compound

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manure, which can be converted into said compound in one stage or in several stages.

R represents the group R or represents a radical, such as a halogen atom, which occurs in one stage or in several stages can be converted to R.

In the synthesis of compounds of structural formulas I and XV by any of the working methods listed above Each group of the starting materials concerned must be compatible with the procedure in question, or, if necessary, it must be protected by a protective group during one reaction stage or several stages and then converted to the desired group ^ * -. Useful examples of groups being protected are the carbonyl groups in the steroid and an amino group from A.

Examples of protective groups for carbonyl groups in the steroids are ketals, e.g. 1,3-dioxolanes, hemioketals, e.g. 1,3-oxathiolane, and dithioketals, e.g. 1,3-dithiolane. 1,3-Dioxolane derivatives can be treated by treating the carbonyl compounds with ethylene glycol in the presence of an acidic catalyst - * are made, and the carbonyl groups can be treated with acids such as

20th
Hydrochloric acid in acetone - to be regenerated again. 1,3-Oxathiolanes can by an acid-catalyzed conversion between

21

see 2-mercaptoethanol and carbonyl compounds - formed and they can be treated with acids such as

22nd
Hydrochloric acid in dioxane -, or by the action of Raney

20th
Nickel - ^ can be converted back into ketones. 1,3-Dithiolanes can be produced by an acid-catalyzed conversion of carbonyl

21
compounds with Äthandithiöl - are made, and the

Carbonyl can later by the action of mercuric - ^ be regenerated.

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Examples of protecting groups for an amino group of A are substituted or unsubstituted benzyloxycarbonyl and benzyl groups. Such N-benzyloxycarbonyl derivatives can by reacting amino compounds with benzyl chloroformate in the presence of an alkaline catalyst

24
and the amino group can later be regenerated by treatment with acidic reagents such as hydrogen chloride —2, or by catalytic hydrogenation. Mono-N-benzyl derivatives can be synthesized by treating the amines with benzyl chloride in the presence of a base and subsequent partial hydrogenation of the dibenzyl compounds formed - * ■; the debenzylation can be accomplished by catalytic hydrogenation.

Of course, one of the steps described above in working methods 1 to 4 or several of these can be used Steps are carried out such that one or both halogen atoms of R by groups such as hydroxyl or sulfone acid ester groups of the same, can be replaced, which can then later be substituted by halogen and so the deliver the desired connection.

The above working methods 1 to 5 can be explained by the following procedures (fi to e):

(a) A process according to working method 1 is characterized in that a compound III or a reactive derivative thereof is reacted in one stage or in several stages with an acid IV or a reactive derivative of such, preferably in the presence of an anhydride or a catalyst.

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2702S09

Examples of reactive derivatives of acid IV are its anhydride or acyl halide, e.g. acylochloride, to cite. A suitable anhydride is trifluoroacetic anhydride and suitable catalysts are, for example, strong organic or inorganic acids such as aryl sulfonic acids or superchloric acid .

The acid IV, in which m is equal to 1, can be prepared by reacting an acid V (equal to acid IV, in which m is zero), or a reactive derivative

4 of the same with a compound VIII, in which R is a suitable

nete carboxyl-protecting group - ^, e.g. a benzyl group, and subsequent removal of the protecting group by a suitable method -2, e.g., catalytic hydrogenation.

VIII

R ^ OCBYC- (A) ₁ - (X)

IV, m - 1

If the group -Y-CO- is an -O-CO group, can group B? be a halogen atom, a hydroxyl group or a reactive ester thereof. If R ^ is a halogen atom, then the acid V is two-dimensionally either in the form of a

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Ion pair before, for example by using an equivalent or catalytic amount of a quaternary ammonium cation as counterion · * -, or in the form of a metal salt, for example one

Q -3,

Alkali or silver salt -. If R- ^{5 is} a hydroxyl group, the acid V is present either as a free acid or in the form of its anhydride or acyl halide, e.g. acyl chloride, and the reaction is preferably carried out in the presence of a carbodiimide, such as dicyclohexylcarbodiimide, or an anhydride, such as trifluoroacetic anhydride, or a catalyst, for example a strong organic or inorganic acid such as an arylsulfonic acid or superchloric acid, or a base such as pyridine, N, N-dimethylaniline or triethylamine - ^ carried out. If Fr is a hydroxyl group which is esterified by an organic acid, for example a sulfonic acid, such as 4-toluenesulfonic acid, or a low molecular weight alkanecarboxylic acid, which is optionally substituted by chlorine or fluorine atoms, such as trifluoroacetic acid, the acid V is expediently either in the form an ion pair, for example with a quaternary ammonium ion as counterion, and the reaction can be carried out in the presence of a catalyst, for example in the presence of a strong acid such as sulfuric acid or 4-toluenesulfonic acid, or a base, for example an aluminum alcoholate, or a quaternary ammonium salt, such as a tetrabutylammonium salt -.

If the group -Y-CO- is an -NH-CO group, then the group R ^ can be an amino group. The acid V is expedient in the form of their anhydride, a mixed anhydride, an ester with low molecular weight alkanols or Alkenols or an acyl halide, e.g. acyl chloride, before. The reaction can be carried out in the presence or absence of a basic catalyst such as pyridine, N, N-dimethylaniline or triethylamine - are carried out.

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If the group -Y-CO- is an -S-CO group, the group can Be for a hydrogen sulfide group. The acid V is either in the form of the free acid or in the form of its anhydride, a mixed anhydride or acyl halide, e.g., acyl chloride. Implementation can either be in the absence or in the presence of a catalyst, e.g. a strong acid such as 4-toluenesulphonic acid, or a base, like pyridine -i-s can be carried out.

(b) A process according to working method 2 is characterized in that a compound II is reacted in one stage or in several stages with an acid V or a reactive derivative thereof, preferably in the presence of a catalyst.

The same working principles described in relation to the formation of the -Y-CO- group in process (a), also apply to the condensation of the groups Fr of the compound II with the -COOH group of the acid V for the purpose of formation the group -Y-CO- of the compound I.

A compound II in which Fr is a halogen atom can be prepared by reacting a 17OC-hydroxy steroid of structural formula III with a halogen acid IX or a reactive derivative thereof in the presence an anhydride such as trifluoroacetic anhydride, or one Catalyst, e.g. a strong organic or inorganic acid, such as an aryl sulfonic acid or superchloric acid - * - *

St - OH + HOOC-B-halogen ^ St - 0-C-B-halogen

III IX II, R ⁵ = halogen

A compound II in which Fr is an -OH group can

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from the corresponding halogen compound (II, Fr = halogen) be produced by working methods known per se, as described, for example, in reference literature 10, or in the following manner: The above halogen compound is formed with a suitable acid such as 4-nitrobenoic acid

ZQ V ..... V «^ v.v ^^. V - or metal salt - implemented to to form a compound X which has a labile ester bond, which is then treated with a suitable base, e.g. potassium tert-butoxide, is hydrolyzed.

St - OCB-Halogen + HOOC-R- ³
II, R ^ = halogen

base
* St - 0-CB-OH

II, B? = OH

Br denotes a group, for example a 4-nitrophenyl group, which makes the adjacent ester bond labile.

Compound II, in which Yir is an -NHp group, can be prepared by converting the corresponding halogen compound (II, Br = halogen) into the corresponding azide (II, Br = N,) using a suitable method, for example by reacting the Halogen compound with sodium azide - and subsequent reduction of the azide to the desired amine. The reduction can be accomplished by reacting the azide with a suitable trivalent phosphorus compound, such as triphenylphosphine or trimethylphosphite, in order to obtain a compound XI which on reaction with water yields a compound II in which R- ^ = NHp.

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N-

St-0-C-B-halogen - II, R- ^ = halogen

- * ► St-O-C-B-N

St - 0-CBN = P (R ⁰ ).

XI

O -►St - O-C-B-NH,

II, R- ⁵ = NH

R stands for an aryl group or a low molecular weight alkoxy group.

A compound II in which R ^ represents an -NHp group, can spontaneously enter into a cyclization, namely on the way of a reaction of the amino group with the keto group in the 20-position of the steroid, so that the cyclic itnin XVIII that can be isolated. The formation of the imine XVIII from the compound II, in the R- * an -NHg group represents is reversible in solution, and in the next reaction step the imine XVIII is converted into the compound II, in which R ^ represents an -NHp group, converted, when the last-mentioned compound is consumed by the reaction with the acid V.

0-C-B-NH,

II, R ⁵ = NH

XVIII

A compound II in which R- ^ is a -SH group can

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from the corresponding halogen compound (II, R = halogen) be prepared according to methods known per se, e.g. by reacting the above-mentioned halide with thiourea for the purpose of forming a compound XII, which is then hydrolyzed

14th
is sated -.

S = C (NH ₂ J ₂

St - OCB-Halogen ► St - CCBSC-NH ₂ -

II, R ^ = halogen XII

-►St - 0-C-B-SH

II, R ⁵ = SH

(c) A process according to working method 3 is characterized in that a halide VI is reacted with a compound VII or a reactive derivative thereof in one stage or in several stages in the presence or absence of a catalyst.

Examples of reactive derivatives of VII are, in the case where the group -X- consists of -0-, ion pairs, e.g. with a quaternary ammonium cation as counterion, and metal salts, e.g. a silver or alkali salt -K A suitable catalyst is, for example, a quaternary ammonium salt, such as a tetrabutylammonium salt.

A halide VI in which m is equal to zero can be prepared by working methods known per se) e.g. by reacting a compound III or a reactive

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'S »

capable derivative thereof with an acid XIII or

1 2 a reactive derivative of such - * -.

St - OH + H00C- (A) _k -halogen ► St - 0-C- (A) _k -halogen

III XIII VI, m = 0

A halide VI in which m and k are equal to 1 can be prepared according to procedures known per se, e.g. by reacting a compound II, which - as indicated above under (b_) - has been prepared with an acid XIII, in which k is 1, or with a reactive derivative thereof. The same working principles as above under (a.) with regard to the formation of the -Y-CO- group also apply to the formation of the group -Y-CO- of the halide VI.

St - 0-C-B-R ^ + HOOC-A-HaIogen ►St -0-C-B-Y-C-A-HaIogen

II XIII, k = 1 VI, m - 1, k = 1

Reaction of a compound II in which Br is —OH, —NH ₂ or —SH and which has been prepared as described above under (bj) with phosgene or its bromine analog yields a halide of the formula VI, in which m equals 1 and k equals zero and Y stands for a -0-, -NH- or -S- group.

jj O = C (halogen) ₂ J? j?

St - OCBR " ⁵ ► St - 0-CBYC-Halogen

II, R ⁵ = OH, NH ₂ or SH VI, m = 1, k = 0

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2? 02b09

(d) A process according to Arbeltsmethode 4, in which a compound m or a reactive derivative of such has a 21-position hydroxyl group, is characterized in that this 17 (X> 21-dihydroxy compound is reacted with such a derivative of acid IV , a 17 * 21-orthoester is formed - the reaction is preferably carried out in the presence of an acidic catalyst, such as sulfuric acid. This cyclic orthoester is then hydrolyzed, for example by the action of an acid, such as oxalic acid, to form the corresponding 17-acyloxy -21-hydroxy compound to give, which then by reductive elimination of the 21-hydroxyl group, for example via the corresponding-

the 21-iodine and 21-p-toluenesulfonate compounds - in one Compound I is transferred.

The acid IV can, as indicated above under (ει), prepared will. Suitable derivatives of IV are, for example, their

1 ft

Orthoesters with low molecular weight alkanols -.

(e) A process according to working method 5 is characterized in that a compound III or a reactive derivative thereof is reacted with an acid XVI or a reactive derivative thereof in one step or in several steps, and in the cases in which R of R is different, the product formed is subsequently converted into a compound XV. The reactions are preferably carried out in the presence of an anhydride or a catalyst.

Examples of reactive derivatives of acid XVI are its anhydride and acyl halide, e.g., the acyl chloride. A suitable anhydride is trifluoroacetic anhydride, and suitable catalysts are e.g. strong organic or other

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organic acids such as aryl sulfonic acids or superchloric acid .

The group R of the acid XVI can be selected from the group R or consist of a halogen atom. If R stands for a halogen atom, then the reaction of a compound III with an acid XVI or a reactive derivative thereof produces a compound XVII which is then converted into a compound XV is converted.

St-0-C-B-Halogen XVlI

A compound XV in which R ^{10 is} an —OH, —SH, —N ₃ or NH ₂ group can be obtained from the compound XVII by the methods described under (b_) above for the preparation of the compound II, in the Έ? for -OH, -SH, -N, or -NHp, from a compound II in which R ^ represents a halogen atom, are given.

A compound XV in which R ¹⁰ denotes an -OH group which is esterified by a carboxylic acid or a sulfonic acid having at most 15 carbon atoms can be obtained from a compound XV in which R is -OH, or from a compound XVII by reaction with a suitable acid or a reactive derivative thereof. Suitable derivatives of the acid for the reaction with the compound XV, in which R represents an -OH group, include its anhydride and acyl halide, for example the acyl chloride, and the reaction is carried out in the presence of an anhydride such as trifluoroacetic anhydride, or a catalyst, For example, a strong organic or inorganic acid, such as an arylsulfonic acid or superchloric acid, or a base, such as pyridine, Ν, Ν-dimethylaniline or triethylamine, carried out. If the acid with the compound XVII

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HO

implemented, it is expediently either in the form of an ion pair, e.g. with a quaternary ammonium cation as Counterion -S or in the form of a metal salt, e.g.

Alkali or silver salt -, before.

A compound XV in which R is an acylamino group with at most 15 carbon atoms or an -SH group esterified by a carboxylic acid or sulfonic acid with at most 15 carbon atoms can be carried out by reacting a suitable acid or a reactive derivative thereof with a compound XV, in which R stands for an —NH ₂ - or —SH group. Suitable derivatives of the acid include its anhydride, mixed anhydride or acyl halide, for example acyl chloride. The reaction can be carried out in the presence or absence of a catalyst, for example a strong acid such as 4-toluenesulfonic acid, or a base such as pyridine.

The compounds of the invention are generally by the pharmacological effectiveness, which is mentioned above, characterized and this gives them their usefulness in combating certain physiological abnormalities in the living animal body. Effective amounts of the pharmacologically active compounds according to the invention can be added to the living Animal are administered in various ways " e.g. orally in the form of capsules or tablets, parenterally in the form of sterile solutions or suspensions and through Implantation of pellets. The routes of parenteral administration also include intravenous, subcutaneous, intramuscular, intraperitoneal, intra-articular and intradermal administration. Other types of administration are vaginal, rectal or external administration, e.g. in the form of ointments, suppositories and powders.

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As examples of living animals with the compounds according to the invention and the agents according to the invention can be treated according to the method according to the invention for the purpose of relieving the pain of the same and / or under conditions similar to those described above, the following may additionally be cited: domestic animals, such as dogs and cats, as well as farm animals such as horses, cows, sheep and goats.

Pharmaceutical formulations are usually prepared from a predetermined amount of one or more compounds according to the invention. Solohe formulations can be in the form of powders, syrups, suppositories, ointments, solutions, pills, capsules, pellets or tablets, suspensions, emulsions, oil solutions etc. with or without, but preferably with any member from the large group of pharmaceutically acceptable vehicles or carriers be prepared. If the active ingredient in admixture with a pharmaceutically acceptable vehicle or carrier is present, should the active ingredient is usually about 0.01 to about 75 wt -.%, Normally about 0.05 to about 15 wt -.% Make up of the composition. In such formulations, carriers such as starch, sugar, talc, commonly used synthetic and natural gums, water and the like can be used. To form tablets, binders such as polyvinylpyrrolidone and lubricants such as sodium stearate can also be used. Substances that promote comminution, such as sodium bicarbonate, can also be incorporated into the tablets.

Albeit relatively small amounts of the active materials of the invention, i.e. amounts down to 5.0 mg, in the case of administration to living beings with a relatively low body weight

709830/0984

HS

but the unit doses are preferably 5 mg or more, preferably 25, 50 or 100 mg or more even more, depending on the nature of the living being treated and the particular result one is to achieve as it is known to the person skilled in the art. Obviously, there are also broader ranges of quantities between 1 and 1000 mg per unit dose are contemplated.

The active ingredients according to the invention can be combined with other pharmacological active ingredients for administration e.g. with analgesics, steroids or hormones or the like, or with buffers, antacids or the like, and the amount of the active ingredient or ingredients in the compositions can be varied widely. It is only necessary that the active ingredient according to the invention is present in an effective amount, i.e. in an amount such that a suitable effective dosage adapted to the dosage form used is achieved. It is obvious that about Multiple unit dosage forms can also be administered at the same time. The exact individual doses and likewise the daily dose will, in any given case, be natural from the well-founded rules of medical science and / or veterinary practice under the supervision of the attending physician or veterinarian. As a general As a rule, in therapeutic use, it can be assumed that the compounds according to the invention in a Amount of 1 to 1000 mg can be administered, with the preferred range 1 to 100 mg per day and living being or patient which is divided into 1 to 4 or more doses over an appropriate time depending on the subject to be treated and the type of living being.

The following examples are intended to explain the invention in more detail, but not to limit it in any way, even if the compounds actually mentioned are of particular concern

709830/0984

meaning for the intended use. These connections have been marked with underlined numbers in the ones listed below biological examples can be reused. The values of the nuclear magnetic resonance spectra given in the examples (NMR data) were obtained from solutions in deuterated chloroform using a 60 MHz instrument (Perkin-Elmer R 12).

example 1

A mixture of 17 <X -hydroxypregn-4-en-3,20-dione (20.0 g) and chloroacetic anhydride (145 g) is heated to 85 ° C. for 22 hours. After cooling, chloroform is added (200 ml) and the solution _{washed with H 2} O and aqueous NaHCO-, dried and evaporated to give an oil which is added with ether (50 ml). The precipitate is filtered off and the filtrate is evaporated to dryness. The residue is dissolved in a mixture of conc. HpSOh (2 ml). Methanol (100 ml) and toluene (100 ml) dissolved. ^{After it has been kept at 50 °} C. for J hours, the solution is evaporated and the residue is dissolved in chloroform (200 ml). After washing with aqueous NaHCO- and HpO, drying and evaporation, an oil is obtained from which, on treatment with ether (25 ml), crystals of 170 <-chloroetoxy-pregn-4-βη 3,20-dione (1. ; 13 * 1 g) separate. After recrystallization from acetone / HpO, the melting point is 216-217 ° C

The structure is confirmed by means of the NMR and IR spectra and the Cl determination. The significant signals of the NMR spectrum are the following: S (ppm) 0.70 (s, JH, H-18), 1.20 (s, 5H, H-19), 2.09 (s, JH, - COCH ₅ ), 4.12 (s, 2H, -CH ₂ Cl), 5.80 (broad s, IH, H-4).

709830/0984

In a substantially analogous manner, the following compounds obtained from the appropriate starting materials. Confirmation of the molecular structures of the compounds was carried out as indicated above.

2_. IJcK -Bromacetoxypregn ^ -en- ^, 20-dione, 2 x 17 <X-chloroacetoxy-6 <X-methylpregn-4-en-5,20-dione, ±. ö-chloro-lToC- (2-chloropropanoyloxy) -pregna-4,6-diene-

3,20-dione,
£. 17 (X- (2-bromopropanoyloxy) -6-methylpregna-4,6-diene- ^, 20-dione,

£. 17 (X-BrOiHaC et oxy-6 o < -f luorpregn-4-en-3,20-dione, £. 6-chloro-17 <X-chloracetoxy-lo-methylenpregna ^, 6-diene-

3,20-dione,
8th_. 17 <K-bromoacetoxy-6-chloro-l6 <X-methyl pregna-4,6-diene-

^, 20-dione and
<£. 6-chloro-17 <K-chloroacetoxy-1 (X, 2 (X-methylenpregna-4,6-diene-3,20-dione.

Example 2

17X-hydroxypregn-4-ene-2,20-dione (80.0 g) is added to a mixture of 4-bromobutyric acid (8o.8 g) and trifluoroacetic anhydride (68.0 ml). After the reaction mixture has been kept at 4 ° C. for 48 hours, it is poured into an ice / dichloromethane mixture. The organic phase is _{washed with H 2} O and aqueous NaHCO, dried and evaporated to give an oil which is dissolved in a mixture of conc. H ₂ SO ^ (4 ml), methanol (200 ml) and toluene (200 ml) is dissolved. After the solution has been left to stand for three hours at 50.degree. C., it is, as described in Example 1, turned on at te ti and 17 (X .- (4-bromobutanoyloxy) -pregn-4-en-3.20 is obtained -dione (Ij 99.0 g) with a melting point of 1J4-1J35 ° C (from acetone / HgO).

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The structure is confirmed by the NMR and IR spectra as well as the
Br determination confirmed. The significant signals of the NMR spectrum are the following: 8 (ppm) 0.70 (s, 3H, H-18),
1.20 (s, 3H, H-19), 2.06 (s, 3H, -COCH ^), 3.48 (t, 2H,
-CH ₂ Br, J = 6 Hz), 5.78 (broad s, IH, H-4).

In a substantially analogous manner, the following compounds obtained from the appropriate starting materials. Confirmation of the molecular structures of the compounds was carried out as indicated above.

2_. 17i> C- (4-chlorobutanoyloxy) -19-norpregn-4-en-3,20-dione,
^. 17 cX - (5-bromopentanoyloxy) -6 (K -fluorpregn-4-en-3 # 20-dione, 4 ^. 170C- (4-bromobutanoyloxy) -oOC-methylpregn ^ -en-J, 20-dione, ^ . 17 <X - (4-bromobutanoyloxy) -e-chlorpregna-4,6-diene-3,20-

dion,
6_. 170 <- (4-bromobutanoyloxy) -e-methylpregna-4,6diene-5.20-

dion and
J_. 170 <- (4-bromobutanoyloxy) -6-chloro-1o <, 2c <-methylenpregna-4,6-diene-3,20-dione.

Example 3

4- / ~ N, N-bis (2-chloroethyl) amino_7-phenylacetic acid (22.1 g) becomes a solution of tetrabutylammonium hydrogen sulfate
(27.2 g) in 2 M NaOH (8o.0 ml). The mixture will
Stirred vigorously for 5 minutes and then with chloroform
(3 × 150 ml) extracted. The dried extract becomes
17 (X-chloroacetoxypregn-4-en-3,20-dione (24.4 g), according to
Example 1 is prepared, added and the mixture heated under reflux for 16 hours. The residue that remains after the solvent has evaporated off is chromatographed on a silica gel column using toluene / ethyl acetate (2: 1) as the eluent. The eluate preparation, which has an R _f value of 0.40, gives the 170C - / "4- (N, N-Bis-

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(2-chloroethyl) -amino ^ phenylacetoxy-acetoxy ^ -pregn-4-en-3,20-dione (Jj 33.4 g) of melting point 72-73 ° C after recrystallization from methanol.

The structure is confirmed by the NMR and IR spectra and the Cl and N determinations. The significant signals of the NMR spectrum are the following: 6 (ppm) 0.70 (s, 3H, H-18), 1.20 (s, 3H, H-19), 2.05 (s, 3H, - COCH ₃ ), 3.65 (s, 1OH, 22-CH ₂ CH ₂ Cl and -OCOCH ₂ ^ -), 4.63 (s, 2H, -OCOCH ₂ OCO-), 5.75 (broad s, IH , H-4), 6.65 (d, 2H, aromatic H, J = 8 Hz), 7.13 (d, 2H, aromatic H, J = 8 Hz).

In an essentially analogous manner, the following compounds are prepared from the corresponding halogen esters of 17ö <-Hydroxysteroids, which according to the procedures of the examples 1 and 2, and the corresponding acids obtained. The structures of the connections are like confirmed above.

2. 17 <X τ £ Τ- (^ - (N, N-Bi s- (2-chloroethyl) -amino) -phenyl) -butanoyloxyacetoxy_7-pregn-4-en-3,20-dlon,

2 17o <- ^ ~ 4- (4- (N, N-bis (2-chloroethyl) -amino) -phenyl) -butanoyloxy) -butanoyloxy_J7-pregn-4-en-3,20-dione,

4_. 17ος - ^ / ~ 4- (4- (N, N-bis- (2-chloroethyl) -amino) -phenylacetoxy) -butanoyloxy_7-pregn-4-en-3,20-dione,

acetoxy-acetoxy_7 ~ pregn-4-en-3,20-dione, 6_. 17 (X - £ ~~ 5- (N, N-bis- (2-chloroethyl) -amino) -benzoyloxyacetoxy_ _i 7-pregn-4-en-3,20-dione,

oxyacetoxy_7'-pregn-4-en-3,20-dione,

8. 6-chloro-17 <X - £ ~ 2- (5- (4- (N, N-bis- (2-chloroethyl) -amino) -phenyl) -pentanoyloxy) -propanoyloxy_7-pregna-4,6- diene-3,20-dione,

709830/098 A

2- 17öC-Z ~ 2 - ((2E) -3- (2- (N, N-bis- (2-chloroethyl) -araino) -phenyl) -propenoyloxy) -propanoyloxy_7 ~ 6-methylpregna-4,6- diene-3,20-dione,

10. 17 O (- ^ 5- (2-Amino-3- (4- (N, N-bis- (2-chloroethyl) -amino) -phenyl) -propanoyloxy) -pentanoyloxy ^ -öoc-f luorpregn-4-en-3,20-dione,

11 ,. 6-chloro-17iK-Z "4- (4- (N, N-bis- (2-chloroethyl) -amino> phenyl) -butanoyloxyacetoxy_7-1 <X, 2O <-methylenpregna-4,6-diene-3, 20-dione,

12. 17-Z ~ (2S) -2-AmInO -? - (4- (N, N-bis- (2-chloroethyl) -amino) -phenyl) -propanoyloxyacetoxy_7-pregn-4-en-5 # 20- dion (made from the corresponding N-benzyl derivative),

12a and its hydrochloride (12a, prepared by treating the free amine with HCl),

13 .. 17 - ^ "4 - ((2S) -2-Amino-3- (4- (N, N-bis- (2-chloroethyl) -atnino) -phenyl) -propanoyloxy) -butanoylOXy _- ^ -pregn -4-en-3,20-dione (made from the corresponding N-carbonyloxybenzyl derivative)

13a and its hydrochloride (13a, prepared by treating the free amine with HCl),

14. 17- / 7 (2S) -2-acetamido-3- (4- (N, N-bis- (2-chloroethyl) -amino) -phenyl) -propanoyloxyacetoxy _-ii 7-pregn-4-en-3 # 20-dion,

£ 1. 17- / ~ 4 - ((2S) -2-acetamido-3- (4- (N, N-bis- (2-chloroethyl) -amino) -phenyl) -propanoyloxy) -butanoyloxy _- 7-pregn-4- en-3,20-dione,

16. 17 ** - £ "* - (4- (N, N-bis (2-chloroethyl) -amino) -phenyl) -butanoyloxyacetoxy ^ Z- 6 UC -methylpregn-4-en-3,20-dione ,

ΐχ. 17 <X - / "4- (N, N-bis- (2-chloroethyl) -amino) phenylaoetoxyacetoxy_7-6-methylpregna-4,6-diene-3,20-dione,

18. 6-chloro-170 <- ^ "3- (N, N-bis (2-chloroethyl) amino) -4-methylbenzoyloxyacetoxy _-> 7-pregna-4,6-diene-3, 20-dione, 17-Z ~ (23) -2-Amino-3- (3- (N, N-bis- (2-chloroethyl) -amino) -

709830/0984

phenyl) -propanoyloxyacetoxy_ / ^r -pregn-4-en-5,20-dione (made from the corresponding N-carbonyloxybenzyl derivative)

19a and its hydrochloride (19a, prepared by treating the free amine with HCl),

20. 17- £ "(2S) -2-AmInO -? - (2- (N, N-bis s- (2-chloroethyl) -amino) phenyl) -propanoyloxyacetoxy_J7-pregn-4-en-3,20ydione (made from the corresponding N-carbonyloxybenzyl derivative)

20a and its hydrochloride (20a, made by treating the free amine with HCl),

21. 17 ^ - ^ 4- (4- (4- (N, N-bis- (2-chloroethyl) -amino) -phenyl) -butanoyloxy) -butanoyloxy _- / -60 ^ -methylpregn-4-en-3 , 20-dione,

22. 6-chloro-17O <- / ~ 4- (4- (N, N-bis- (2-chloroethyl) -amino) -

phenylacetoxy) -butanoyloxy_7-pregn-2,4-dlen-3,20-dlon, £ 2. 1JO (- £ ~ k- (5- (N, N-BIs- (2-chloroethyl) -amino) -4-methylbenzoyloxy) -butanoyloxy_J7-6-methylpregna-4,6-diene-3,20-dione,

24. 6-Chloro-170C-Z " ⁴ " (M * - (N, N-bis- (2-chloroethyl) -amino) -phenyl) -butanoyloxy) -butanoyloxy ^ -1 (X, 20C -methylenepregna-4 , 6-diene-3,20-dione,

2 ^. 170 <- / ~ 4-chloro-3- (N, N-bis- (2-chloroethyl) -amino) -benzoyloxyacetoxy __ ^ '- 60 (-fluoropregn-4-ene-3,20-dione and

26, 17 <X ~ -Z 3 - (^ - (N, N-bis (2-chloroethyl) amino) phenoxy) -propionyloxyacetoxy _- 7-pregn-4-ene-3,20-dione.

Example 4

A mixture of 17 <X-chloroacetoxypregn-4-en-J, 20-dione (40.7 g) # prepared according to Example 1, and NaN, (32.6 g) in 60 mg acetone (500 ml) is 16 hours under back

709830 / 098A

river heated. The acetone is removed by evaporation and the aqueous solution with a 1: 1 ether / ethyl acetate mixture (3 x 100 ml) extracted. The combined extracts are washed with HgO, dried and evaporated to give an oil, from which crystals of 170C-azidoacetoxypregn-4-ene-3,20-dione (22.0 g) separate out on treatment with ether.

A solution of triphenylphosphine (25.2 g) in benzene (100 ml) is added dropwise to a solution of the ob ^ h azide (32.0 g) in benzene (200 ml). After refluxing for 4 hours, the solution is cooled to room temperature and HCl is bubbled through the solution until precipitation begins. Ether is then added to complete the precipitation and the crystals formed are collected. The product is dissolved in dichloromethane and, after washing with aqueous NaHCO 3 and HpOi, drying and evaporation, the l-oxa-4-azacyclohex-3-en-6-one £ (9.40 g) is obtained a spontaneous intramolecular condensation of the 17o <-Amlnoacetoxypregn-4-en-3 * 20-dione has been formed. The structure of the compound / V is confirmed by its NMR spectrum: <5 (ppm) 0.97 (s, 3H, H-18), 1.19 (s, 3H, H-19), 2.27 (s , JH, CH ₃ -C = N-), 4.14 and 4.48 (doublets, each 1H, AB system with J = 22 Hz, -N-CH ₂ -CO-), 5.75 (broad s , IH, H-4).

OCCH ₂ NH ₂

709830/098;

so

Compound A_ (9.4O g) is dissolved in a mixture of acetone (240 ml) and 0.15 M aqueous KCl (120 ml). The p _H is maintained constant by addition of 5 M HCl constant at 4.2. When the consumption of HCl has ceased, a solution of 4- ^ 4- (N, N-bis- (2-chloroethyl) -amino) -phenylJ7-butyric anhydride (22.0 g) in acetone (200 ml) is added and the p "was kept at 4.2 by the constant addition of 5 M NaOH. When the consumption of NaOH has ceased, the acetone is removed by evaporation, and the aqueous Lot solution is extracted with a 1: 1 ether / ethyl acetate mixture (3 × 100 ml). The extract is washed with 1 M aqueous NaCO-. and HgO washed, dried and evaporated. The residue is triturated in refluxing isopropyl ether and then recrystallized from an ethyl acetate / isopropyl ether mixture, and the 17CX - ^ ~ 4- (4- (N, N-bis- (2-chloroethyl) -amino) -phenyl) is obtained. -butanoylaminoacetoxy _ / - pregn-4-en-; 5j20-dione (jj 8.85 g; decomposes on heating).

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The structure is confirmed by the NMR and IR spectrum as well as the Cl and N determination. The significant signals of the NMR spectrum are the following: β (ppm) 0.68 (s, 3H, H-18), 1.18 (s, 3H, H-19), 2.05 (s, 3H, - COCH ₅ ), 3.65 (s, 8h, 2 -CH ₂ CH ₂ Cl), 4.03 (d, 2H, -COCH ₃ N <, J - 6 Hz), 5.74 (broad s, IH, H-4), 6.16 (t, IH,> NH, J - 6 Hz), 6.64 (d, 2H, aromatic H, J = 7 Hz), 7.05 (d, 2H, aromatic H, J = 7 Hz).

In an essentially analogous manner, the following compound is made from the corresponding halo ester 17O <-hydroxysteroids - prepared according to Example 1 - and obtained the corresponding acid. The structure of the connection is confirmed as stated above.

2.170C - / 3- ( ^N ' ^N - ^Bls - ( ² - ^cnlor P ^r ° Py ¹ ) -amino) -4-methylbenzoylaminoacetoxy ^ -0 <-methylpregn-4-ene-3,20-dione.

Example 5

4-Nitrobenzoic acid (13-4 g) is added to a solution of tetrabutylammonium hydrogen sulfate (27.2 g) in 2 M NaOH (80.0 ml). The mixture is stirred vigorously for 15 minutes and then extracted with chloroform (3 × 150 ml). 17 <? <- bromoacetoxypregn-4-en-3,20-dione (27.2 g) - prepared according to Example 1 - is added to the dried extract. After refluxing for 24 hours, the solution is washed with H ₂ O, 2.5 MH ₂ SO ₄ , H ₂ O, aqueous NaHCO 3 and HgO, then dried and evaporated. When a 1: 1 mixture of toluene and ethyl acetate (100 ml) is added to the residue, crystals of ITX - (4-nitrobenzoyloxyacetoxy) -pregn-4-en-3 * 20-dlon (29.1 g) separate out.

709830/0984

- ¥ s- 2702609

The above-mentioned 4-nitrobenzoic acid ester (29.1 g) is dissolved in a mixture of tert-butanol (4300 ml) and H _? O (700 ml) and 1 M KOH (58 ml) is added dropwise with stirring. After standing for 16 hours at room temperature, HgO is added and the solution is extracted with chloroform (5 × 1000 ml). The combined extracts are dried and evaporated, and a 1: 1 mixture of toluene and ethyl acetate (120 ml) is added to the residue. After standing for 16 hours at room temperature, the crystals of 17EX -Hydroxyacetoxypregn-4-en-3,20-dione (11.0 g; melting point 220 to 221 ° C) are filtered off. The compound has the following significant NMR signals: S (ppm) 0.70 (s, j5H, H-18), 1.19 (s, 3H, H-19), 2.06 (s, 3H, - COCH,), 4.22 (s, 2H, -0-COCH ₂ -), 5.31 (s, IH, OH), 5.75 (broad s, IH, H-4).

Another 17o <-Hydroxyacetoxypregn-4-en-3 * 20-dione (2.6 g) is isolated from the piltrate by chromatography on a silica gel column using a 1: 2 toluene / ethyl acetate mixture as the eluent (R _f = 0 , 25) received.

The above alcohol is aoetylated with acetic anhydride in pyridine to obtain the 17CX-acetoxyacetoxypregn-4-ene-3,20-dione, which shows the following significant NMR signals: £ (ppm) 0.69 (s, 3H, H -18), 1.19 (s, 3H, H-19), 2.07 and 2.17 (singlets, each 3H, 2-COCH,), 4.65 (s, 2H, -0.00.CH ₂ - ), 5.76 (broad s, IH, H-4).

A solution of the above alcohol (13.6 g) in absolute benzene (200 ml) is treated ^{with phosgene at 5 ° C.} After standing at room temperature for 16 hours, the solution becomes

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- ■ sr-

evaporated "to give a crystalline residue, from the treatment with ether 17 <X -Chlorcarbonyloxyaoetoxypregn-4-en-j5,20-dione (14.2 g) is obtained.

A solution of the above chloroformate (14.2 g) in dry chloroform (100 ml) is added dropwise with stirring at 0 ⁰ C to a mixture of N, N-bis (2-chloroethyl) -4-phenylenediamine hydrochloride (11.4 g ) and triethylamine (7.95 g) in dry chloroform (100 ml) were added. After standing at room temperature for 16 hours, the solution is washed _{with H 2} O, 2 M HCl and H _{2 O.} After drying and evaporation, an oil is obtained which is chromatographed on a silica gel acid using toluene / ethyl acetate (2: 1) as the eluent. The fraction with an R _f value of 0.28 gives the 17 * - ^ "V (N, H-Bi s- (2-chloroethyl) -amino) -phenylcarbamoyloxyacetoxy ^ / - pregn-4-en-3.20 -dione (I ₁ ; 7 * 35 g; melting point 104-105 ° C).

The structure is confirmed by the NMR and IR spectrum as well as the Cl and N determination. The significant signals of the NMR spectrum are the following: S (ppm) 0.66 (s, JH, H-18), 1.13 (s, 3H, H-19), 2.08 (s,} H, -COCH ₃ ), 3.66 (s, 8h, 2 -CH ₂ CH ₂ Cl), 4.68 (s, 2H, -OCOCHgOCO-), 5.69 (broad s, IH, H-4), 6 , 64 (d, 2H, aromatic H, J = 9 Hz), 7.27 (d, 2H, aromatic H, J = 9 Hz) i

In an essentially analogous manner, the following compounds are obtained from the corresponding halogen esters of the 17CX-hydroxysteroids - prepared according to Example 1 - and the corresponding 4-phenylenediamine or 4-aminophenol. The structures of the compounds have been confirmed as stated above.

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2. 6-chloro-17 "- ^ f4- (N, N-bis- (2-chloroethyl) -aralno) -2-methoxy phenyl car bamoy 1 oxy ac et oxy_J7-16 -me thy1enpregna-

4,6-diene-3,20-dione,
^. o-chloro-ITO ^ -C ^ - ( ^N 'N-bis- (2-chloroethyl) -amino) -phenoxycarbonyloxyacetoxy ^ -loöC-methylpregna- ^ io-diene-

^, 20-dione and
4 .. 17 <* - / "4- (N, N-bis- (2-chloroethyl) -amino) -phenoxycarbonyloxyacetoxy__7-pregn-4-en-3,20-dione.

Example 6

NaN (3 × 25 g) is added to a solution of tetrabutylammonium hydrogen sulfate (17.0 g) in 5 M NaOH (10.0 ml). The solution is extracted with dichloromethane (100 ml) and toluene (100 ml) is added to the dried extract. The dichloromethane is removed by evaporation and 17 * X - (4-bromobutanoyl oxy) -pregn-4-ene-3,20-dione (17.2 g) - prepared according to Example 2 - is added to the toluene solution. After standing for 20 hours at room temperature, the solution is _{washed with H 2} O, dried and evaporated. On treatment with ether, the residue yields <- (4-azidobutanoyloxy) -pregn-4-en-3,20-dione (14.2 g).

A mixture of trimethyl phosphite (5.8 g), the above azide (14.2 g) and toluene (1 ^ 0 ml) is heated J, hours at 85 ⁰ C. The solution is evaporated and methanol (250 ml) and 1 M HCl (250 ml) are added to the residue. After 3 hours of treatment at 45 ° C., the methanol is evaporated off, the aqueous solution is washed with ethyl acetate and the aqueous phase is extracted with dichloromethane. After drying and evaporation of the extract, YJOC - (4-aminobutanoyloxy) -pregn-4-en-3,20-dione hydrochloride (29.1 g) is obtained.

709830/0984

The above amine hydrochloride is acetylated with acetyl chloride to give the IJ (K - (4-acetylaminobutanoyloxy) -pregn-4-ene-3,20-dione, which shows the following significant NMR signals: S (ppm) 0.65 (s. 3H, H-18), 1.19 (s, 3H, H-19), 2.00 and 2.10 (singlets, each 3H, 2-COCH,), 5.70 (broad s, IH , H-4), 7.42 (broad t, IH, NH).

A mixture of acetone (1200 ml) and 0.15 M KCl (400 ml) is treated with 4- ^ f "N, N-bis (2-chloroethyl) -amino _- 7-P ⁿ enylacetic anhydride (42.8 g) The ρ of the solution becomes

H adjusted to 6.0 and a solution of the above amine hydrochloride (29.1 g) in a mixture of acetone (1200 ml) and 0.15 M KCl (400 ml) is added. The p "is kept at 6.0 to 6.5 by the constant addition of 5 M NaOH. When the consumption of NaOH has ceased, the acetone is removed by evaporation and the aqueous solution is extracted with ethyl acetate (2400 ml). The organic phase is _{washed with 1 M Na 2} CO- and H ₂ O, dried and evaporated and yields the 17 ^ - ^ * 4- (4- (N, N-bis- (2-chloroethyl) -amino) - phenylacetylamino) -butanoyloxy_7-pregn-4-en-3,20-dione (I ₁ ; 41.0 g; decomposes on heating).

The structure is confirmed by the NMR and IR spectrum as well as the Cl and N determination. The significant signals of the NMR spectrum are the following: S (ppm) 0.65 (s, JH, H-18), 1.19 (s, 3H, H-19), 1.99 (s, 3H, - COCH ₅ ), 3.37 (s, 2H, -COCH ₂ <p-) _t 3.69 (s, 8h, 2-CH ₂ CH ₂ Cl), 5.70 (broad s, IH, H-4) , 6.68 (d, 2H, aromatic H, J - 9 Hz), 7.17 (d, 2H, aromatic H, J = 9 Hz).

In an essentially analogous manner, the following compounds are prepared from the corresponding halogen esters of the 1JO (- hydroxysteroids - according to Example 2 - and the

709830/0984

corresponding acids obtained. The structures of the compounds have been confirmed as above.

G. 17 (X - / ~ 4- (2- (4- (N, N-bis- (2-chloroethyl) -amino) -phenyl) -2-methylpropanoylamino) -butanoyloxy _e J7-19-noi'pregn-4- en-

3,20-dione,
2 · 17 <X -C ^ - (^ "(N, N-Bi s- (2-bromoethyl) -amino) -4-methylbenzoylatnino) -pentanoyl OXy _- J ^ -O (\ -fluoropregn-4-en- 3 * 20-

dion and
H. YJOC- ^ h- (3- (N, N-bis- (2-chloroethyl) -amino-4-methylbenzoylamino) -butanoyloxy_7-pregn-4-ene-5,20-dione.

Example 7

A mixture of 3- / ~ "N, N-bis- (2-chloroethyl) -amino_J7-4-methylbenzoic acid (27.6 g) and trifluoroacetic anhydride (21.0 g) is heated to 60 ° C. for 15 minutes while stirring. 17 X -Hydroxypregn-4-ene-^, 20-dione (16.5 g) is added to the mixture and the mixture is stirred and heated to 80 ° C. for 5 hours, then toluene (150 ml) is added The solution is filtered and the filtrate is treated with chloroform (200 ml). After washing with HoO and aqueous NaHCO- ,, drying and evaporation, an oil is obtained, to which a mixture of methanol (300 ml) and conc. HCl (j5 ml) is obtained. After standing at room temperature for ΐβ hours, the solution is evaporated and the residue is chromatographed on a silica gel column using toluene / ethyl acetate (2: 1) as the eluent. The eluate fraction, which has an R _f value of 0.4o, provides the 17 <X- £ "3- (N, N-bis- (2-chloroethyl) -amino) -4-methylbenzoyloxy-7-pregn-4-en-3,20-dione (1; 6.8 g; melting point 170 - 171 ° C).

The structure is confirmed by the NMR and IR spectrum as well as the Cl and N determination. The significant signals of the NMR spectrum are as follows: S (ppm) 0.75 (s, ^ H, H-18), 1.23 (s, 3H, H-19), 2.00 (s, ^ H , -COCH ₃ ), 2.40 (s,

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3H, aromatic CH ^), 3.45 (s, BH, 2-CH ₂ CH ₂ Cl), 5.76 (broad s, IH, H-4), γ,} 4 (d, IH, aromatic H, J = 8Hz), 7.71 (dd, IH, aromatic H, J ¹ = 8 Hz and J ² = 2 Hz), 7.86 (d, IH, aromatic H, J = 2 Hz).

In a substantially analogous manner, the following are made

Compounds _{A obtained from} the appropriate starting materials. The molecular structures of the compounds have been confirmed as above.

2.17cxT - / P * - (N, N-Bi s- (2-chloroethyl) -amino) -phenylacet-

oxy_7 ~ pregn-4-en-3,20-dione,
3_. 17 <X - / ~ 4- (4- (N, N-bis (2-chloroethyl) -amino) -phenyl) -

butanoyloxy_7-pregn-4-en-2,20-dione, 4. 17 <X- ^ ~ 4- (3- (N, N-bis- (2-chloroethyl) -amino) -4-methyl-

benzoyloxy) -butanoyloxy_7'-pregn-4-en-3 »20-dione and 5_. 17- ^ ~ (2S) -2-acetamido-3- (4- (N, N-bis- (2-chloroethyl) -amino) -phenyl) -propanoyloxy__7-pregn-4-en-3 * 20-dione.

Example 8

HgO (10.8 g) is added to a mixture of 1,2-dimethoxyethane (125 ml) and 70% HClO _{1 ^ (6.5 g).} The mixture is 25 minutes at 45 under stirring - heating 55 ⁰ C and after that cooled down to room temperature. Then 1,7OC- (4-bromobutanoyloxy) -pregn-4-en-3 * 20-dione (24.0 g) - prepared according to Example 2 - and H ₃ O (10 ml) are added, and the reaction mixture becomes 5 Stirred for hours at room temperature. Chloroform (100 ml) is then added, the mixture is filtered and the filtrate is washed _{with HpO, aqueous NaHCO-, and H 3 O.} The residue obtained after drying and evaporation is chromatographed on a silica gel column using toluene / ethyl acetate (1: 4) as the eluent. The 17Ö <(4-hydroxybutanoyloxy) -pregn-4-ene-3,20-dione (13 * 6 g;

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Melting point 16-162 ° C) from an eluate fraction that has an R ^ value of 0.20. The structure is confirmed by the NMR and IR spectrum. The following NMR signals are significant: <5 (ppm) 0.68 (s, ^ H, H-18), 1.20 (s, 3H, H-19), 1.99 (s, 3H, -COCH ^), 4.19 (t, IH, OH, disappears on addition of HCOOH), 5.70 (broad s, IH, H-4).

The alcohol is acetylated with acetic anhydride in pyridine and gives the 17 <X- (4-acetoxybutanoyloxy) -pregn-4-en-3,20-dione, which shows the following significant NMR signals: ei (ppm) 0.69 ( s, 3> H, H-l8), 1.19 (s, 3H, H-19), 2.02 and 2.06 (singlets, each 3H, 2-COCH,), 4.1> (t, 2H, -CH ₂ OCO-), 5.75 (broad s, IH, H-4).

Example 9

This example illustrates the effect of the compounds of general formula I with respect to the inhibition of the Growth of tumors.

The LD50 is the dose that has a 50 # latality of the Animals, and the ED50 is the dose that will cause a 50% reduction in tumor size.

It is evident from the numerical values given below that the compounds have very low toxicity and that the therapeutic indices (T.I.), i.e. the ratios LD50: ED50, are very high.

The experimental procedure and the interpretation of the results are carried out in accordance with the standards, which the CCNSC (Cancer Chemotherapy Reports, January 1959

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and December 1962).

Some of the results obtained are summarized in the tables below. The connections are through a Code number a: denotes b, where a indicates the example in which the connection in question is established and b refers to the order of the compounds made according to this example are related. The code no. 4: 2 the second compound which was produced according to Example 4. The systematic names of the compounds are given in the examples.

This example illustrates that the new compounds are useful in disrupting the growth of tumors and to suppress it, and that in some cases they even bring about a complete remission of the tumors and therefore they can be used to treat live animals suffering from diseases that are based on a Response to treatment with anticancer agents and immunosuppressive agents.

Table I. Walker carcinosarcoma 256

Experimental animals: Sprague-Dawley rats. Tumor implant; Tumor pieces 2-4 mm in diameter,

subcutaneous.

Therapy t administered by os daily for 5 days, starting on the day following the implantation. End of trial; The animals were sacrificed on day 9. Evaluation; The tumor weights of the test animals are compared with those of control animals.

7 0 9 8 3 0/0 9 8 A

Results

LD50 ED50 T.I. link > 25O 8th > 3i 3: 1 > 250 3 > 83 3: 2 4o 2 20th 3: 3 8o 4th 20th 3: 4 > £ 50 16 > 15 3: 7

The following further compounds also have an antitumor activity in the test described above for: 3: 5, 3: 6, 3:11, 3:12, 3: l4, j $: l6, 3:18, 3:21, 4: 1, 5: 1, 6: 1 and 7: 4.

Table II Hepatoma AH

Experimental animals: Sprague-Dawley rats.

Tumor implant: 5 x 10 tumor cells ip

Therapy: One ip injection on the day following the implantation.

End of the experiment: The animals were sacrificed on the 8th day. Evaluation: The tumor weights of the test animals are compared with those of control animals.

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Results

LD50 ED50 Τ.Ι. link > 250 3 > 83 3: 1 > 1000 100 > 10 3: 2 180 6th 30th 3 x 3 50 2 25th 3 x 4 > 250 50 > 5 3 x 5 > 250 2 > 125 3 χ 7 > 250 125 > 2 4: 1 > 250 30th > 8 5 χ 1 > 250 16 > 15 7 χ 4

The following further compounds also have an antitumor activity in the test described above on: 3: 6, 3x8, 3x9, 3x10, 3x13, 3x15, 3x17, 3x19 * 3x20, 3x22, 3x23, 3x24, 3x25, 3:26, 4: 2, 5: 2, 5x3, 5 · χ4, 6 * 2, 6x3, 6: 4 and 7: 1.

Table III Ehrlich Asoites tumor ELD hyperdiploid (46 chronosomes)

Versuohatiere t SPF NMRI mice. Tumor implant: 2 × 10 tumor cells ip Therapiet an Ip injection on the implantation

the following day.

Versuohsende: The animals were killed on the 8th day. Evaluation: The tumor weights of the test animals were compared with those of control animals.

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Results

Compound dose mortality tumor weight

/ /. % treated / control

3: 1 50 1/12 3 3: 2 50 0/12 1 3: 7 100, 0/12 2 5: 1 1000 0/12 1 7: 1 1000 0/12 5 7: 2 1000 0/12 3 7: 3 1000 0/12 5

The other compounds below also show anti-tumor activity in those described above Test: 3: 3, 3: 4, 3: 5, 3: 6, 3: 8, 3: 9, 3:11, 3:12, 3:14, 3:16, 4: 1, 5: 1, 5: 4, 6: 1, 6: 4, 7: 4 and 7: 5-

Table IV Lymphatic leukemia L 1210

Experimental animals: CDF ₁ (C3HxDBA / 2) F, -Mouse.

Tumor implant: 10 ^ tumor cells ip

Therapy: One ip injection on the day following the implantation.

Evaluation: (a) The survival time of the test animals (t),

expressed as a percentage of those of the control animals (c).

Effect (*) -

(b) Change in weight in the test animals (T) compared to that of the control animals (C) up to the 5th day. Δ _ν - T - C.

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(c) The mortality rate in the test animals does not have to exceed 35% on the 5th day of therapy.

He results

Compound Dose Mortality Weight Effect (mg / kg) ^ ^d ^ r ^g W

3: 7 500 0/19 -5.2 172 250 0/20 -4.0 130

Example 10

This example illustrates the relative affinity of the compounds for the rabbit uterine cytosolic progesterone receptor compared to progesterone. The method used for this purpose represents a modification of the methods which have already been described by K. Kontula and colleagues (Acta Endocrinol. J8 (1975) 574) and L. Terenius (Steroids 2 £ (1974) 909), among others.

Cytosol production

Female rabbits (3-4 pounds), supplier Knut Larsen, Uddevalla, Sweden, were injected with 1 mg eatradurin (polyestradiol phosphate; 1 mg / ml saline, AB Leo, Sohwe den). After a week the animals were tutted and the uteri were immediately removed, frozen and dissected free of connective tissue. All of the following operations were performed at 0-4 ° C. The uteri were cut into small pieces and repeated several times with 3 volumes of one

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Buffer at p _H 7, k washed containing 50 mM TRIS-HCl, 1.5 mM EDTA, 3 mM NaN ,, 2 mM dithiothreitol and 25% glycerol (vol .- #) contained. The tissue was homogenized in the same buffer (3 VolL) with four 15 s bursts with a rheostat setting 36-37 of an Ultra Turrax device (Janke and Kunkel KO, Staufen, Germany). The homogenate was centrifuged in a Sorvall GLC-2 centrifuge for 15 minutes at 600 χ g. The supernatant liquid was centrifuged again at 105,000 g for 60 minutes in a Beokman ultracentrifuge, model LB-65-B with SW 56 rotor.

1 ml portions of the supernatant liquid (rabbit uterine cytosol) were pipetted into small glass centrifuge tubes and stored at -70 ⁰ C until use. The protein content was determined by the Lowry method (J. Biol. Chem. 193 (1951) 265).

Solve the links

10.0 mg of each compound was dissolved in 10.0 ml of 99 * 5% ethanol. 100 μl of this standard solution were diluted to 5.0 ml of ethanol / glycerol (volume ratio 1: 1). The ethanol was evaporated by blowing air on the solution at 40 ° C. The volume was then adjusted to 5.0 ml by adding the buffer without glycerol.

Incubation of the compounds

The compounds were tested with Olycerin / buffer (1 t 1) to

-8 - * 5 final concentrations between 10 and 10 'M diluted in a total of 300 μl incubation medium. 100 / ul of each compound and the dilution were placed in small centrifuge tubes

2 ml) incubated together with 100 / ul (10 pg) -progesterone (1,2,6,7-3H-progesterone; 47.8 Ci / mmol,

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«J

The Radioohemical Center, Amersham, England) and lOOyul Cytosol «with the buffer to a final concentration of set about 0.7 g / ml. The incubations were 16 to Carried out at 4 ° C for 18 hours.

The separation of the bound from the free radioactivity was carried out at ⁰ ° C. using the "dextran epated oharooal technique (DCC)". 0.5 ml of DCC suspension (0.05 % Dextran-70, Pharmaoia, Uppsala, Sweden, and 0.5 % Norit A, Sigma, Saint Louis, Missouri, USA) was added to each incubation tube. The tubes were shaken 2-3 times for 10 minutes, after which they were centrifuged at 100 χ g for 5 minutes. The supernatant liquids were decanted directly into solntillation vessels (polyethylene, Packard) which contained 10 ml InstaOel (Packard). Badioactivity was counted in a Philip's liquid scintillation spectrometer model PW 4510/00 with external standard and automatic Lösoh correction.

Standard curve for progesterone

In incubation tubes 100 / ul Cytosol, 100 / ul ^ H-progesterone (10 pg) and 100 / ul of various dilutions of non-radioactive progesterone in olcerin / buffer (1: 1), which were from 0 to 10 pg / 100 / ul, were given. The tubes were incubated in parallel with the compounds described above. The radioactivity was calculated by subtracting the radioactivity counted in the incubation tubes from the radioactivity in the incubation tubes in which the cytosol is transported through the Buffer had been replaced (100 / µl) was counted.

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Calculations

The concentration of the non-radioactive progesterone ^ "" P_71 * ^{dle equals} 5 ° % of ^the bound radioactive progesterone (competes for) was calculated from the equation

= 0.5

calculated standard curve, where £ ~ B_J ^ is the bound radioactivity at different concentrations of the non-radioactive progesterone and £ ~ Β_ / _{Ο represents} the bound radioactivity at the progesterone concentration zero.

Samples for each compound X were constructed in an analogous manner, and the concentration for each compound containing 50 % bound - ^ H-progesterone (/ ~ X_7) was equal to-

50 comes, calculated.

The relative binding affinity (RBA), expressed as a percentage, was calculated for each substance in comparison to progesterone, and the values obtained are summarized in the table below.

Tabel

RBA 0.6 link 0.7 3 0.9 3: 1.1 7 ι 1.8 4! 2.4 3 ι 3.6 7! 6.3 7! 6.6 7 y 15.8 3 ι 5 ι »3 : 2 ! 4th : 1 ! 7th : 2 ! 1 ! 3 ι 1 t 1

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From this example it can be seen that the connections have the ability to specifically concentrate in tumor cells that are rich in progesterone receptors, as they are often found in breast tumors and uterine tumors.

Example 11

Manufacturing method for tablets of 10 mg Model approach for 1000 tablets

Connection 3: 7, mesh size 70 * ' Milk sugar, Ph. Nord. Corn starch, Ph. Nord. Kollidon 25, BASF Aqua purificata as required Talc, Ph. Nord Magnesium stearate, Ph. Nord

Weight of 1000 tablets: 315 g Weight of one tablet: 315 mg

* 'The Masohen standard corresponds to the international one Code system DIN 4189/1968.

Tablet shape: 10.5 mm round; flaoh; notched; faets.

10, 0 G 210 G 75 G 3, 5 G 15th β 1. 5 G

The sieved substances I are thoroughly smelted and then moistened with II, after which the Oanze through a No. 10 screen (25 mesh) made of stainless steel is granulated. The granules are then placed in a drying cabinet dried at a maximum of 40 ° C. and the sieving through sieve no. 10 repeated. «

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The substances listed under III are then added and mixed in thoroughly. Then tablets with a gross weight of about 315 mg are pressed.

Example 11a

The procedure is as in Example 11 above, with the modification that the compound 3 s 7 is replaced by the compound JtI .

Example 12 Injectable solution 10 mg / ml

Compound 3t2, 70 mesh 10 mg

Benzyl alcohol 80 mg

Peanut oil to make up to 1 ml

The substance is dissolved in the benzyl alcohol and the peanut oil is added.

example 12a

It is worked up as in Example 12 with the modification that the compound is 3 * 2 duroh rsetzt compound 7 ι •.

Example 13 25 mg vaginal balls

Compound 4: 1 25 mg

Cocoa butter as needed

Example 13a

The composition is the same as in the above example 13 with the modification that the compound 4 χ 1 is replaced by the compound 7 * 3.

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Example 14 Ointment 2- <ig

Compound 5il 2 g

Triethanolamine 1 g

Glycerin 7 g

Cetanol 2.5 g

Lanolin 2.5 g

Stearic acid 20 g

Sorbitan monooleate 0.5 g

Sodium hydroxide 0.2 g

methyl p-hydroxybenzoate 0.3 g

Propyl p-hydroxybenzoate 0.1 g

Ethanol 0.9 g

Water to make up to 100 g

Example 14a

The composition is the same as in Example 14 above, with the modification that the compound is 5 * 1
is replaced by the connection 7 ι 4.

Example 15 10 mg capsules

Connection 3 «2 10

Magnesium stearate 2 ng

Talc 188 ng

The substances are mixed together and filled into capsules.

Example 15a

The composition is the same as in Example 15 above with the modification that the compound 3 ι 2 is replaced by the compound 7 ι 1.

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Example l6 Injectable solution 15 mg / ml

Compound 5 O 15 Benzyl benzoate 120 mg Rioinus oil to make up to 1 ml

The compound is dissolved in the benzyl benzoate and the castor oil is added.

Example l6a

The composition is the gleiohe as "that compound 3 '3 is replaced with compound 7 * 2 in the above Example 16 with the modification.

In the above Examples 11 to 16a, the compounds contained in the agents are according to the numerical code as defined in Example 9. Of course, Examples 11 to 16a only serve as an explanation with regard to the active ingredients cited by way of example. It goes without saying that the other compounds which are disclosed in the preceding examples j5 to 7, instead of the active ingredients whose use is illustrated in the above examples.

It goes without saying that two or more compounds according to the invention can be used in combination with one another in the agents listed for illustration and that these compounds, if desired, also in combination with other pharmacologically active substances substances can be used.

It goes without saying that those skilled in the art with regard to the connections, means and methods of

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present invention, numerous modifications and equivalents are known, without thereby affecting the principle the present invention is departed from, and the invention is therefore by no means limited to the specific examples and limit the disclosed embodiments.

Compilation of those cited in the description Reference literature

1. A.J. Solo and J.O. Gaiter, J. Pharm. Soi. 6o (1971) IO89.

2. Huang-Minlon, E. Wilson, N.L.Wendler and M.Tishler, J.A.C.S. J4 (1952) 5394.

5. S.R. Sandler and W. Karo, Organic Functional Group Preparations; Academic Press, New York 1971 # Chapter 2.

4. R. Vitali, R. Qardi, and A. Ercoli, Oazz. ChIm. Ital. 26 (1966) III5.

5. J.F.W. McOmie, Protective Groups in Organic Chemistry; Plenum Press, London 1973

6. C. Djerassi, Steroid Reactions; Holden-Day, San Francisco 1963 * Chapter 1.

7. A. Brandström. Preparative Ion Pair Extraction; Apotekarsocieteten / Hässle Läkemedel, Sweden 1974, page 109.

8. Reference literature 3, page 252.

9. Reference 3, page 247.

10. A. MoKillop and M.E. Ford, Tetrahedron ^ O (1974) 2467.

11. Reference literature 3 # page 274.

12. J.H. Boyer and J.Hamer, J.Amer.Chem.Soo. 21 (1955) 951 ·

13. A. SohOberl and A. Wagner in E. Müller (editor) Methods of Organic Chemistry (Houben-Weyl), Volume (1955) 749.

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14. D.D. Reynolds, J.Org.Chem. 2J_ (I962)

15. Reference literature 5, chapter

16. A. McKillop, J.-C. Piaud and R.P. Hug, tetrahedron 22 (1974) 1379.

17. CA. Buehler and D.E. Pearson, Survey of Organic Syntheses; Wiley, New York 1970, 287.

18. E.H. Cordes in S. Patai (Editor) The Chemistry of Carboxylic Acids and Estersj Wiley, London I969, Chapter 13.

19. N. Sulzbaoher, E.D. Bergmann and E.R. Pariser, J.Amer. Chem. Soc. JO (1948) 2827.

20. O.J. Rosenkranz, J. Pataki and D.Djerassi, J.Org.Chem. ΐχ (1952) 290.

21. L.F. Fieser, J. Amer. Chem. Soc. J6 (1954) 1945.

22. RH Mazur and EA Brown, J. Amer. Chem. Soc. J_J_ (1955) 6670.

23. E.J. Corey and R.B. Mitra, J. Amer. Chem. Soc. (1962) 2938.

24. E. Wünsch in E. Müller (Editor), Methods of organic chemistry (Houben-Weyl), Volume XV / l, page

25. Y. Levin, A. Berger and E. Katonalski, Biochem. J.63 , (1956) 308.

26. E. Baer, J. Maurukas, and M. Russell, J. Amer. Chem. Soo.

24 (1952) 152.

27. HJ Haas, Chem. Ber. £ 4 (I96I) 2442.

28. CA. Buehler and DE Pearson, Survey of Organic Syntheses; Wiley, New York 1970, p.814.

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Claims (45)

Claims 1. '17OC esters of gestagens of the general formula - ^y ' St - R, ^v Χ / in which R is a group of the formula .1 stands in which R is a ß- or γ-halogen-substituted Denotes an alkyl group having 2 to 4 carbon atoms and the halogen consists of chlorine or bromine; R is a hydrogen atom, a low molecular weight alkyl group, low molecular weight Represents an alkoxy group or a halogen atom; A for a straight hydrocarbon chain with at most 4 carbon atoms, which is saturated or has a double bond, and where at most two Hydrogen atoms of A are replaced by low molecular weight alkyl groups and at most one of the hydrogen atoms, bonded to the carbon atom adjacent to a -C0 group through an amino group or a low molecular weight alkanoylamino group is replaced; B is a straight, saturated hydrocarbon chain with at most 4 carbon atoms and at most 2 hydrogen atoms of B by low molecular weight Alkyl groups are replaced; X and Y independently of one another denote a -0-, -NH- or -S- radical; k, m and η denote, independently of one another, a number with a value of zero or 1 and η is always zero if k and m are equal to zero; and finally St stands for the remainder of a steroid having a cyclopentanophenanthrene carbon-carbon skeleton has, which is a maximum 709830/0984 ORIGINAL INSPECTED 27Q2bO9 Contains 40 carbon atoms including the substituents and said carbon-carbon skeleton represents the carbon-carbon skeleton of a steroid nucleus, which in turn consists of a pregnan or 19 norpregn anchors, which have zero to a maximum of 4 double bonds, and the said steroid residue is bonded in its 17-position to the group R, wherein the position mentioned is designated according to the usual steroid nomenclature. 2. Compound according to claim 1, characterized in that said steroid residue is a carbon-carbon skeleton has, which consists of the carbon-carbon skeleton of Pregn-4-ene, Pregna-4,6-diene or 19-Norpregn-4-ens exists. 3. Compound according to claim 2, characterized in that that said steroid residue St has a core which is from the substance group of the Pregn-4-en-3,20-dione, Pregna-4,6-diene-5i20-dione and 19-norpregn.-4-en-5,20-dione cores is selected and said steroid residue St attaches said residue R to the steroid nucleus in said steroid nucleus Contains 17-position bound. 4. Compound according to claim 3 # characterized in that that any further substitution that occurs in the carbon-carbon skeleton of said steroid nucleus of said Steroid residue is present, at most a tetrasubstitution, with as those positions of the steroid-carbon-carbon skeleton, which are substituted, the 1-, 2-, 6-, 7-, 16- or 21-positions come into question and the substitution - if one has occurred at all - by at least a substituent from the radical group methyl, ethyl, methylene, fluorine and chlorine has taken place. 709830/0984 5. Compound according to claim 4, characterized in that that said steroid residue St consists of a residue of 17-hydroxypregn-4-en-j5,20-dione, 17-hydroxy-6 <X -methylpregn-4-en-5,20-dione, 6-chloro-17-hydroxypregna-4,6-diene-3,20-dione, 17-Hydroxy-6-methylpregna-4,6-diene-3,20-dione or 6-chloro-17-hydroxy-16o <-methylpregna-4,6-diene-3,20-dione consists. 6. A compound according to claim 5 »characterized in that that the symbol R representing a β-halogen-substituted alkyl group is derived from a β-halogen-substituted Ethyl, n-propyl or n-butyl group; Pure Represents hydrogen atom or a low molecular weight alkyl group; the -NR p group is in the m or p position, if k and η are equal to zero and are in the p-position, if at least one of the symbols k and η is equal to 1; 2 1 R when the -NR «group is in the m-position, is in the p-position; furthermore in the case where A is replaced by an amino group or a low molecular weight alkanoylamino group is substituted, η is zero and A represents a saturated hydrocarbon chain which Contains 2 carbon atoms; the symbol X - provided there is is present - stands for a -0- or -NH radical and the symbol Y - if it is present - for a -0- or -NH radical. 7. Connection according to claim 6, characterized in that that R is a ß-ChioräthyIgruppe. 8. A compound according to claim 7 *, characterized in that m is equal to 1. 9 · Connection according to claim 8, characterized in that η is zero. 709830/0984 10. A compound according to claim 4, characterized in that it consists of a representative of the substance group 17 <X - / ~ 2 - ((2E) -3- (2- (N, N-bis- (2-chloroethyl) -amino) -phenyl) -propenoyloxy) -propanoyloxy _- _y ^r -6-methylpregna-4 _J 6-diene-3,20-dione, 6-chloro-17o <- ^ "4- (4- (N, N-bis- ( 2-chloroethyl) amino) -phenyl) -butanoyloxyacetoxy_J7-1C <* 2c <-methylenepregna-4,6-diene-3,20-dione and 17 <x- / ~ 5-O (N, N-bis- (2 -bromoethyl) -amino) -4-methylbenzoylamino) -pentanoyloxy_J7- -fluorpregn-4-en-3,20-dione. 11. A compound according to claim 6, characterized in that it consists of 17- / T3- (N, N-bis (2-chloropropyl) amino) -4-methylbenzoylaminoacetoxy ^ T-oCX -methylpregn-4-en-5,20-dione consists. 12. A compound according to claim 7, characterized in that it consists of 17 - ^> (N, N-bis (2-chloroethyl) amino) -4-methylbenzoyloxy__7-pregn-4-en-3,20-dione, 17 - ^ f "4- (N, N-bis- (2-chloroethyl) -amino) -phenylacetoxyJZ-pregn ^ -en-3,20-dione, 17- ^ f" 4- (4- (N, N- Bis- (2-chloroethyl) -amino) phenyl) -butanoyloxy_7-pregn-4-en-3,20-dione or 17- ^ (2S) -2-acetamido-3- ( 4- (N, N-bis s - (2-chloroethyl) -amino) -phenyl) -propanoyloxy_7 ~ pregn-4-en-3,20-dione consists. 13. Compound according to claim 8, characterized in that that they consist of 17-Zr " ⁴ - ( ^N ' ^N - ^bis - ( ² - ^cnloräth y ¹ ) - ^amln °) -phenylthioacetoxyacetoxy__7-pregn-4-en-3,20-dione or n- £" ^ - ( 4 - (N, N-bis (2-chloroethyl) -amino) -phenoxy) -propionyloxyacetoxy _< _7 "pregn-4-en-5,20-dione. 14. A compound according to claim 8, characterized in that it consists of 17- / ~ 4- (N, N-bis (2-chloroethyl) amino) phenylcarbamoyloxyacetoxy_7-pregn-4-en-5,20-dione, 709630/0984 6-chloro-17- ^ ~ 4- (N, N-bis- (2-chloroethyl) amino) -2-methoxyphenylcarbamoyloxyacetoxy ^ -lo-methylenepregna-4,6-diene-3,20-dione or 17 - / "4- (N, N-bis- (2-chloroethyl) -amino) -phenoxycarbonyloxyacetoxy ^ Z-pregn - ^ - en - ^, 20-dione consists. 15 · Compound according to claim 9 # characterized in that it consists of 17-Z ~ 3- ( ^N » ^N - ^bis - (2-chloroethyl) -amino) -benzoyloxyace toxy_J ^r -pregn-4-en-3,20-dione , 17-Z ""} - (N, N-bis (2-chloroethyl) amino) -4-methylbenzoyloxyacetoxy _ ^ - pregn-4-en-3,20-dione, 6-chloro-17- ^ f " 3- (N, N-bis- (2-chloroethyl) -amino) - ^ - methylbenzoyloxyacetoxy ^ -pregna-4,6-diene-3,20-dione or 17- ^ 4- (XN, N-bis- (2-chloroethyl) -amino) -4-methylbenzoyloxy) -butanoyloxy_7-pregn-4-ene-3,20-dione. 16. A compound according to claim 9, characterized in that it consists of H- ^ h- (3-N, N-bis- (2-chloroethyl) -amino) -4-methylbenzoylaraino) -butanoyloxy_7 ~ pregn-4-en-3 “20-dione exists. 17 · Compound according to claim 9 *, characterized in that it consists of 17-Z ~ ^ - ( ^N * ^N -B ^is - ( ² - ^cnloräth y ¹ ) - ^aniln0 ) -phenylacetoxyaoetoxy_7-pregn-4-en-3,20- dione, 17- ^ f 4- (4- (N, N-Bi s- (2-chloroethyl) -amino) -phenyl) -butanoyloxyacetoxy_7-pregn-4-ene-3,20-dione, 17- / "V (4- (4- (N, N-Bi s- (2-chloroethyl) -amino) -phenyl) -butanoyloxy) -butanoyloxy_7-pregn-4-en-3,20-dione, 17-Z ~ 4- ( 4- (N, N-bis (2-chloroethyl) amino) phenylacetoxy) butanoyloxy 7-pregn-4-ene-3,20-dione, 17- ^ f "((2S) -2-amino-3 - (4- (N, N-bis- (2-chloroethyl) -amino) phenyl) -propanoyloxy) -acetoxy_7 ~ pregn-4-en-3 # 20-dione or its hydrochloride or 709830/0984 from 17-Z ~ 4 - ((2S) -2-amino -} - (4- (N, N -bis s- (2-chloroethyl) -amino) -phenyl) -propanoyloxy) -butanoyloxy_7-pregn-4- en-3,20-dione or its hydrochloride, from 17 - ^ "((2S) -2-acetamido-5- (4- (N, N-bis- (2-chloroethyl) -amino) -phenyl) propanoyloxy) -acetoxy_J7'-pregn-4-en-3 * 20-dione, 17- ^ ~ 4- (4- (N, N-Bi s- (2-chloroethyl) -amino) -phenyl) -butanoyloxyacetoxy ^ -ooi- methylpregn-4-en-3,20-dione or 17- ^ ~ 4- (N, N-bis- (2-chloroethyl) -amino) -phenylacetoxyacetoxy_7-6-methylpregna-4,6-diene-3,20- dion exists. 18. Compound according to claim 9> characterized in that it consists of 17 - ^ "4- (4- (N, N-bis (2-chloroethyl) amino) phenyl) butanoylaminoacetoxy _> _7-pregn-4-en -3,20-dione, 17- / ~ 4- (4- (N, N-bis- (2-chloroethyl) -amino) -phenylacetylamino) -butanoyloxy__7-pregn-4-en-3,20-dione or IT - ^ h- (2- (4- (N, N-bis- (2-chloroethyl) -amino) -phenyl) -2-methylpropanoylamino) -butanoyloxy _> _7 ^ -19-norpregn-4-en-3 * 20 -dion exists. 19. Steroid derivatives of the general formula St-OCBR ¹⁰ , in the St means the remainder of a steroid having a cyclopentanephenanthrene-carbon-carbon skeleton which contains a maximum of 40 carbon atoms including the substituents and wherein said Carbon-carbon skeleton from the carbon-carbon skeleton of a nucleus, which in turn consists of the nucleus of the Pregnans or 19-Norpregnans exists and both nuclei have zero to a maximum of 4 double bonds, said steroid residue in 709830/0984 its 17-position attached to the -O-CO-B-R group and this position is designated according to the usual steroid nomenclature; furthermore B is a straight, saturated one Hydrocarbon chain means that at most 4 Koh-r has lenstoffatome, with at most 2 hydrogen atoms of B replaced by low molecular weight alkyl radicals are; R stands for a hydroxyl or mercapto group or one by a carboxylic acid or sulfonic acid with at most 15 carbon atoms esterified hydroxyl or mercapto group, an amino group or an acylamino group with a maximum of 15 carbon atoms or an azido group, and such heterocyclic compounds, obtained by a cyclization reaction of R including any amino group present and the keto group in the 20-position of the steroid residue have been formed. 20. A compound according to claim 19, characterized in that said steroid residue is a carbon-carbon skeleton has, which consists of the carbon-carbon skeleton of Pregn-4-ene, Pregna-4,6-diene or 19-Norpregn-4-ens exists. 21. Compound according to claim 20, characterized in that said steroid residue St has a core, that from the nucleus of Pregn-4-en-5,20-dione, Pregna-4,6-diene-5,20-dione or 19-norpregn-4-en-3> 20-dione and the said steroid residue St the named -0-CO-B-K ^ - Contains group bound to said steroid nucleus in said 17-position. 22. A compound according to claim 21, characterized in that any further substitution that occurs in the carbon 700830/0984 Carbon skeleton of said steroid nucleus of said Sterol residue is present, is at most a tetrasubstitution and as those positions of the steroid carbon-carbon skeleton, which are substituted, the 1-, 2-, 6-, 7-, 16- or 21 positions come into question and substitution - if such has occurred at all - by at least one representative from the radical group methyl » Ethyl, methylene, fluorine and chlorine is done. 23. Compound according to claim 22, characterized in that that said steroid residue St consists of a residue of 17-hydroxypregn-4-en-] 5,20-dione, 17-hydroxy-6o <-methylpregn-4-en-3,20-dione, 6-chloro-17-hydroxypregna-4,6-diene-2,20-dione, 17-hydroxy-6-methylpregna-4,6-diene-5,20-dione or 6-chloro-17-hydroxy-16 <X-methylpregna-4,6-diene-3,20-dione consists. 24. Compound according to claim 23, characterized in that that they are made of ^ -Hydroxyacetoxypregn ^ -en-}, 20-dione, 17- (4-Hydroxybutanoyloxy) -pregn-4-en-3> 20-dione, 17-aoetoxyacetoxypregn-4-en-3 * 20-dione, 17 "(4-acetoxybutanoyloxy) -pregn-4-en-j5» 20-dione, 17-Aminoaoetoxypregn-4-en-3,20-dione, 17- (4-aminobutanoyloxy) -pregn-4-en-3,20-dione, 17- (4-acetamidobutanoyloxy) -pregn-4-ene-3,20-dione, 17-azidoacetoxypregn-4-ene-j5,20-dione or 17- (4-azidobutanoyloxy) -pregn-4-en-3 # 20-dione consists. 25. Pharmaceutical agent, characterized in that it is one or more compounds according to as active ingredient Claim 1 in combination with a pharmaceutically acceptable carrier and - if desired - other pharmacological products Contains active ingredients. 709830/0984 26. Method of treating a live animal «that a disease that responds to anticancer and immunosuppressive treatment , characterized in that said animal is given a therapeutically effective amount of a compound administered according to claim 1. 27. A process for the preparation of the compounds claimed in claim 1, characterized in that that he (A) a steroid of the formula St-OH, in which St has the meaning given in claim 1, or a reactive one Derivative of the same with an acid of the general formula HO- (ö-BY) _m -C- (A) _k - (X) _n - S f Λ \ (IV), 1 2
in which A, B, X, Y, R, R, k, m and η have the meanings given in Claim 1, or a reactive derivative thereof, preferably in the presence of an anhydride such as trifluoroacetic anhydride, or a catalyst, eg a strong one Acid, such as an arylsulfonic acid or superchloric acid, is reacted; or one (b) in the case where η is 1, a halide of the general formula St-O- (C-B-Y) -C- (A), - halogen (VI), Iu IC in which St, A, B, Y, k and m have the meanings given above and halogen is chlorine or bromine means with a compound of the general formula 709830/0984 (VII), 1 2 in which X, R and R have the meanings given above, or a reactive derivative thereof, preferably in the presence of a catalyst such as a quaternary ammonium salt for the purpose Reacts formation of the desired compound; or one (c) in the case in which m is equal to 1, a compound of the general formula St-O-C-B-R ^ (II), in which St and B have the meanings given above and Br represents a group which, together with a -COOH group, is able to generate a -Y-CO group in one stage or in several stages, with an acid of the general formula HOOC- (A) _k - (X) _n <(^ ^ (V), 1 2
in which A, X, R, R, k and η have the meanings given above, or a reactive derivative thereof, preferably in the presence of an anhydride such as trifluoroacetic anhydride, or a catalyst, for example a strong acid such as an arylsulfonic acid or superchloric acid, or a base such as pyridine, Ν, Ν-dimethylanllin or triethylamine, to form the desired compound; or one 709830/0984 (d) in the pall in which the compound St-OH in 21-position is hydroxy-substituted, said Compound St-OH, in which St has the meaning given above, or a reactive derivative the same with an orthoester of an acid of the general formula 1 2 in which A, B, X, Y, R, R, k, m and η have the meanings given above, or a reactive derivative thereof, preferably in the presence of a catalyst, for example an acid such as sulfuric acid, to form a 17 # 21 -Orthoesters implemented, which then in a known manner in the desired compound is converted * where in the compounds of the formulas St-OH, II, IV, V, VI and VII any sensitive groups present are protected during the above-mentioned reactions and then the desired group is exposed again. 28. The method according to claim 27, characterized in that the step (o) listed there is carried out with the proviso that in the general formula given therein R ^ for a halogen atom, an OH group, an OH- esterified by an organic acid Group, an NH ₂ - or SH group, where halogen has the meaning given in claim 27. 29. The method according to claim 28, characterized in that the symbol R ^ means a halogen atom and the 709830/0984 -4fr- Acid V in the form of an ion pair, e.g. with a quaternary Ammonium cation as a counterion, or in the form a metal salt, for example an alkali or silver salt, is present and halogen is that given in claim 27 Has meaning. 30. The method according to claim 28, characterized in that the symbol Br represents an OH group which is substituted by an organic acid, for example a sulfonic acid such as 4-toluenesulfonic acid, or a low molecular weight alkanecarboxylic acid, which is optionally substituted by a chlorine or fluorine atom , such as trifluoroacetic acid, is esterified, and the acid V is either present as a free acid or in the form of an ion pair, for example with a quaternary ammonium cation as a counterion. jjl. Process according to claim 28, characterized in that the symbol denotes an OH, NH ₂ or SH group and the acid V is present either as a free acid or in the form of its anhydride or acyl halide, e.g. acyl chloride, and the reaction is preferably in the presence a carbodiimide such as dioyclohexylcarbodiimide, an anhydride such as trifluoroacetic anhydride, or a catalyst, for example a strong organic or inorganic acid such as an arylsulfonic acid or superchloric acid, or a base such as pyridine, N, N-dimethylaniline or triethylamine. 32. The method according to any one of claims 27 to Jl, characterized characterized in that said steroid residue has a carbon-carbon skeleton consisting of the carbon-carbon skeleton of the Pregn-4-ene, Pregna-4,6-diens or 19-norpregn-4-ens. 709830/0984 33 · The method according to claim 32, characterized in that that said steroid residue St has a core which is composed of the core of Pregn-4-en-3,20-dione, Pregna-4,6-diene-3,20-dione or 19-norpregn-4-en-3,20-dione and said steroid residue St consists of the residue R on said steroid core in said 17-position contains bound. 34. The method according to claim 33 * characterized in that that any further substitution occurring in the carbon-carbon skeleton of said steroid nucleus of said Steroid residue is present, at most a tetrasubstitution, with as those positions of the steroid carbon-carbon skeleton, which are substituted, the 1-, 2-, 6-, 7-, 16- or 21-positions come into question and the substitution - if one has occurred at all - by at least a substituent from the radical group methyl, ethyl, methylene, fluorine or chlorine has taken place. 35 · The method according to claim 34, characterized in that said steroid residue St from the remainder of 17-hydroxypregn-4-en-3,20-dione, 17-Hydroxy-6ö <-methylpregn-4-en-3,20-dione, 6-chloro-17-hydroxypregna-4,6-diene-3,20-dione, 17-Hydroxy-6-methylpregna-.4,6-diene-3,20-dlons or 6-chloro-17-hydroxy-16oc-methylpregna-4,6-diene-3,20-dione consists. 36. The method according to any one of claims 27 to 35, characterized in that the one ß-halogen-substituted Symbol R representing an alkyl group from a β-halogen-substituted one Ethyl, n-propyl or n-butyl group; 709830/0984 ρ
R represents a hydrogen atom or a low molecular weight alkyl group; the -NR p-group is in the m- or p-position when k and η are equal to zero, and is in the p-position when at least one of the symbols 2 1 bole k and η is 1; R when the -NR "group is in the m-position, is in the p-position; furthermore in the case where A is replaced by an amino group or a low molecular weight alkanoylamino group is substituted, η is zero and A is a saturated hydrocarbon chain represents having two carbon atoms; the symbol X - if it is available for is an -O- or -NH- radical; and the symbol Y - if it is present - for a -0- or -NH radical stands. 37 · The method according to claim 36, characterized in, that R is a ß-chloroethyl group. 38. The method according to any one of claims 27 to 37 * thereby characterized in that m is equal to 1. 39. The method according to any one of claims 27 to 38, characterized in that η is equal to zero. 40. Steroid derivatives of the general formula St-OCBR ¹⁰ , in the St means the remainder of a steroid having a cyclopentanephenanthrene-carbon-carbon skeleton which contains a maximum of 40 carbon atoms including the substituents, and wherein said Carbon-carbon skeleton from the carbon 709830/0984 Carbon skeleton consists of a nucleus, which in turn consists of the nucleus of the Pregnane or 19-Norpregnans exists and both nuclei have zero to a maximum of 4 double bonds, furthermore said steroid residue bound in its 17-position to the -O-CO-B-R group and this position according to the usual steroid nomenclature is designated; also B is a straight, saturated hydrocarbon chain with a maximum of 4 carbon atoms means, with at most 2 hydrogen atoms are replaced by low molecular weight alkyl radicals; R stands for a hydroxy or mercapto group or a through a carboxylic acid or sulfonic acid with a maximum of 15 carbon atoms esterified hydroxyl or mercapto group, an amino group, an acylamino group having at most 15 carbon atoms, an azido group, and such heterocyclic compounds produced by a cyclization reaction of R including any amino group present and the keto group in the 20-position of steroid residue have been formed. 41. A compound according to claim 40, characterized in that said steroid residue is a carbon-carbon -Skeleton, which consists of the carbon-carbon skeleton of Pregn-4-ene, Pregna-4,6-diene or 19-Norpregn-4-ens exists. 42. A compound according to claim 41, characterized in that said steroid residue St has a core which from the core of Pregn-4-en-3,20-dione, Pregna-4,6-diene-3,20-dione or 19-norpregn-4-en-3,20-dione and wherein said steroid residue St is said -0-CO-B-R group contains bound to said steroid nucleus in said 17-position. 709830/0984 43- connection according to claim 42, characterized in that that any further substitution occurs in the carbon-carbon skeleton of said steroid nucleus of said Steroid residue is present, at most a tetra substitution, and as those positions of the steroid-carbon-carbon skeleton, which are substituted, the 1-, 2-, 6-, 7-, 16- or 21-positions come into question and the substitution - if such a thing has occurred at all - by at least one Representatives from the radical group methyl, ethyl, methylene, fluorine or chlorine has taken place. 44. Compound according to claim 4}, characterized in that that said steroid residue St consists of a residue of 17-hydroxypregn-4-en-3> 20-dione, 17-hydroxy-6 (X-methylpregn-4-en-3 * 20-dione, 6-chloro-17-hydroxypregna-4,6-diene-3 * 20-dione, 17-Hydroxy-6-methylpregna-4,6-diene-3,20-dione or 6-chloro-17-hydroxy-16 (X'-methylpregna-4,6-diene-3,20-dione consists. 45. A compound according to claim 44, characterized in that it consists of 17-hydroxyacetoxypregn-4-en-3,20-dione, 17- (4-Hydroxybutanoyloxy) -pregn-4-en-3,20-dione, 17-Acetoxyaoetoxypregn-4-en-3,20-dione, 17- (4-acetoxybutanoyloxy) -pregn-4-en-3 # 20-dione, 17-aminoacetoxypregn-4-en-3,20-dione, 17- (4-aminobutanoyloxy) -pregn-4-en-3,20-dione, 17- (4-acetamidobutanoyloxy) -pregn-4-ene-3,20-dione, 17-azidoacetoxypregn-4-ene-3 * 20-dione or 17- (4-azidobutanoyloxy) -pregn-4-en-3 # 20-dione consists. 709830/0984